Obesity affects over 25% of adult women in the United States and continues to increase in prevalence. Minority women are disproportionately affected by obesity: 37% of African American women and 33% of Mexican American women are obese (body mass index equal to or more than 30 kg/m2). In addition to cardiovascular risks, obese women clearly are at increased risk for developing endometrial cancer. Obese women have a 9-10% lifetime risk of endometrial cancer and account for almost 50% of all cases. It is presumed that the increased peripheral conversion of adrenal steroids to estrone in adipose tissue, the increased bioavailability of adrenal steroids, and the increased bioavailablity of free estrogens due to decreased sex hormone binding globulin (SHBG) contribute to a "hyper-estrogenic state", resulting in the development of endometrial hyperplasia and endometrial cancer. However, excess circulating estrogens are unlikely to fully account for this increased cancer risk. We hypothesize that insulin resistance and hyperinsulinemia are causally related factors that promote endometrial carcinogenesis by altering estrogen regulated pathways in the endometrium. In addition, we hypothesize that correction of insulin resistance may be a rational cancer chemopreventive strategy for obese women. We plan to identify, using an animal model of obesity and insulin resistance, molecular markers in the endometrium associated with dysregulated estrogen-controlled growth pathways. A clinical chemoprevention trial will be performed to determine if normalization of insulin resistance is accompanied by modulation of surrogate biomarkers. Aim 1: To test the hypothesis that obesity and insulin resistance increase estrogen-dependent proliferation in the endometrium. Animal models of obesity and insulin resistance will be used to evaluate the effects of obesity on estrogen-regulated endometrial gene expression. In addition, the ability of insulin sensitizers to reverse this effect will be studied. Specific genes involved in estrogen-regulated proliferation pathways will be examined by quantitative PCR, including hormone receptors and co-activators, and genes involved in the Wnt pathway, IGF pathway, TGF-beta and retinoid pathway. Aim 2: To identify novel genes and pathways associated with insulin resistance and estrogenization, and to identify relevant and specific biomarkers that are modulated by normalization of insulin resistance. Expression profiling with cDNA microarrays will be used to explore the effects of obesity and insulin resistance on both estrogen-dependent and estrogen-independent endometrial gene expression. In addition, specific biomarkers of the endometrium that are modulated by insulin-sensitizers will be identified. Aim 3: To assess the ability of an insulin-sensitizing agent to modulate surrogate endometrial biomarkers in a post-menopausal cohort of obese, insulin resistant women. The post-menopausal cohort includes obese women (body mass index equal to or more than 30kg/m2) who demonstrate insulin resistance based on an oral glucose tolerance test, but who do not fulfill criteria for Type II Diabetes. We hypothesize that rosiglitazone, an insulin-sensitizing agent, will modulate relevant endometrial proliferation biomarkers. In pre-and post-treatment endometrial biopsies, we will assess expression levels of genes involved in estrogen-regulated gro,aedapathways, specific biomarkers as defined in Aim 2, and histologic and proliferation markers. As secondary endpoints, we will establish a point estimate of the baseline frequency of endometrial abnormalities in this cohort and we will determine changes in serum levels of estradiol, estrone, testosterone, DHEA-S and SHBG in obese, post-menopausal women taking rosiglitazone.